Publications by authors named "Peter Hersey"

154 Publications

A combination of epigenetic BET and CDK9 inhibitors for treatment of human melanoma.

J Invest Dermatol 2021 Mar 26. Epub 2021 Mar 26.

Melanoma Immunology and Oncology Program, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Electronic address:

Dysregulation of epigenetic modifiers is a frequent event in melanoma and underlies many aspects of melanoma biology including resistance to targeted and immunotherapies. Here we report that dual targeting of BET and CDK9 proteins have synergistic effects against melanoma cells in vitro and in vivo. The BET inhibitor (IBET151) and CDK9 inhibitor (CDKI73) synergistically killed melanoma cells in vitro independent of their BRAF or NRAS mutation status. The combination of drugs markedly inhibited the growth of human melanoma C002M cells in vitro in 3D spheroids and in vivo in NSG mice compared to vehicle control and the individual drugs (p<0.05). Cell death was associated with mitochondrial depolarisation and caspase dependent apoptosis with cleavage of PARP1 as well as downregulation of anti-apoptotic proteins BCL2, BCLXL and MCL1. GSEA revealed downregulation of hallmark gene-sets associated with E2F, G2M checkpoint and c-MYC. Survival analysis showed worse prognosis with high G2M, E2F or c-MYC gene signatures suggesting biomarkers of response of BET and CDK9 inhibitors in melanoma. This combination of epigenetic inhibitors targets multiple downstream genes leading to cell death of melanoma cells in vitro and in vivo and warrant further investigation for treatment of melanoma in patients not responding to current therapies.
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http://dx.doi.org/10.1016/j.jid.2020.12.038DOI Listing
March 2021

Sex bias of females in survival from cancer and infections. Is X the answer?

Br J Cancer 2021 03 19;124(7):1184-1186. Epub 2021 Jan 19.

Melanoma Oncology and Immunology Program, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, 2050, Australia.

Major differences in survival of men and women from infectious diseases and cancers have been highlighted by death rates from COVID-19 infections. In cancer, attention has been focussed on differences in gene expression from X chromosomes in men and women with a preponderance of genes involved in immune responses being expressed in women. Important findings have been that some of the genes are important epigenetic regulators that play fundamental roles in immune responses.
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http://dx.doi.org/10.1038/s41416-020-01245-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813969PMC
March 2021

Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma.

Eur J Cancer 2021 Feb 24;144:182-191. Epub 2020 Dec 24.

Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, Wollstonecraft, NSW, 2065, Australia; Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, 610 University Ave, Toronto, ON, M5G2C1, Canada; The Kinghorn Cancer Centre at St Vincent's Hospital, 370 Victoria St, Darlinghurst, NSW, 2010, Australia; St Vincent's Clinical School, UNSW Sydney, Victoria St, Darlinghurst, NSW, 2010, Australia. Electronic address:

Objective: Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.

Patients And Methods: Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.

Results: Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.

Conclusions: These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.

Clinical Trial Registry: NCT01295827, NCT01704287, NCT01866319.
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http://dx.doi.org/10.1016/j.ejca.2020.11.010DOI Listing
February 2021

Study of the Female Sex Survival Advantage in Melanoma-A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts.

Cancers (Basel) 2020 Jul 28;12(8). Epub 2020 Jul 28.

Melanoma Oncology and Immunology Program, The Centenary Institute, The University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia.

Background: Survival from melanoma is strongly related to patient sex, with females having a survival rate almost twice that of males. Many explanations have been proposed but have not withstood critical scrutiny. Prior analysis of different cancers with a sex bias has identified six X-linked genes that escape X chromosome inactivation in females and are, therefore, potentially involved in sex differences in survival. Four of the genes are well-known epigenetic regulators that are known to influence the expression of hundreds of other genes and signaling pathways in cancer.

Methods: Survival and interaction analysis were performed on the skin cutaneous melanoma (SKCM) cohort in The Cancer Genome Atlas (TCGA), comparing high vs. low expression of , , and . The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort.

Results: Analysis of TCGA data revealed that two of these genes- and -were associated with improved survival from melanoma. Tumoral was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance of and its interaction with but also revealed the expression of and to be prognostically significant. The analysis also confirmed a partial correlation of with immune tumor infiltrates.

Conclusion: When considered together, the results from these two series are consistent with the involvement of X-linked epigenetic regulators in the improved survival of females from melanoma. The identification of gene signatures associated with their expression presents insights into the development of new treatment initiatives but provides a basis for exploration in future studies.
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http://dx.doi.org/10.3390/cancers12082082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464825PMC
July 2020

EZH2 Cooperates with DNA Methylation to Downregulate Key Tumor Suppressors and IFN Gene Signatures in Melanoma.

J Invest Dermatol 2020 12 29;140(12):2442-2454.e5. Epub 2020 Apr 29.

Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Electronic address:

The histone methylase EZH2 is frequently dysregulated in melanoma and is associated with DNA methylation and silencing of genes involved in tumor suppression. In this study, we used chromatin immunoprecipitation and sequencing to identify key suppressor genes that are silenced by histone methylation in constitutively active EZH2 mutant melanoma and assessed whether these regions were also sites of DNA methylation. The genes identified were validated by their re-expression after treatment with EZH2 and DNA methyltransferase inhibitors. The expression of putative EZH2 target genes was shown to be highly relevant to the survival of patients with melanoma in clinical datasets. To determine correlates of response to EZH2 inhibitors, we screened a panel of 53 melanoma cell lines for drug sensitivity. We compared RNA sequencing profiles of sensitive to resistant melanoma cells and performed pathway analysis. Sensitivity was associated with strong downregulation of IFN-γ and IFN-α gene signatures that were reversed by treatment with EZH2 inhibitors. This is consistent with EZH2-driven dedifferentiated invasive states associated with treatment resistance and defects in antigen presentation. These results suggest that EZH2 inhibitors may be most effectively targeted to immunologically cold melanoma to both induce direct cytotoxicity and increase immune responses in the context of checkpoint inhibitor immunotherapy.
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http://dx.doi.org/10.1016/j.jid.2020.02.042DOI Listing
December 2020

Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma.

J Immunother Cancer 2020 04;8(1)

Ludwig Institute for Cancer Research Austin Branch, Heidelberg, Victoria, Australia.

Background: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.

Methods: Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.

Results: The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4 and CD8 responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)/Human Leukocyte Antigen (HLA) class I double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.

Conclusions: The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.
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http://dx.doi.org/10.1136/jitc-2019-000410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204806PMC
April 2020

Co-targeting bromodomain and extra-terminal proteins and MCL1 induces synergistic cell death in melanoma.

Int J Cancer 2020 10 24;147(8):2176-2189. Epub 2020 Apr 24.

Melanoma Immunology and Oncology, The Centenary Institute, Camperdown, New South Wales, Australia.

The treatment of melanoma has been markedly improved by the introduction of targeted therapies and checkpoint blockade immunotherapy. Unfortunately, resistance to these therapies remains a limitation. Novel anticancer therapeutics targeting the MCL1 anti-apoptotic protein have shown impressive responses in haematological cancers but are yet to be evaluated in melanoma. To assess the sensitivity of melanoma to new MCL1 inhibitors, we measured the response of 51 melanoma cell lines to the novel MCL1 inhibitor, S63845. Additionally, we assessed combination of this drug with inhibitors of the bromodomain and extra-terminal (BET) protein family of epigenetic readers, which we postulated would assist MCL1 inhibition by downregulating anti-apoptotic targets regulated by NF-kB such as BCLXL, BCL2A1 and XIAP, and by upregulating pro-apoptotic proteins including BIM and NOXA. Only 14% of melanoma cell lines showed sensitivity to S63845, however, combination of S63845 and I-BET151 induced highly synergistic apoptotic cell death in all melanoma lines tested and in an in vivo xenograft model. Cell death was dependent on caspases and BAX/BAK. Although the combination of drugs increased the BH3-only protein, BIM, and downregulated anti-apoptotic proteins such as BCL2A1, the importance of these proteins in inducing cell death varied between cell lines. ABT-199 or ABT-263 inhibitors against BCL2 or BCL2 and BCLXL, respectively, induced further cell death when combined with S63845 and I-BET151. The combination of MCL1 and BET inhibition appears to be a promising therapeutic approach for metastatic melanoma, and presents opportunities to add further BCL2 family inhibitors to overcome treatment resistance.
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http://dx.doi.org/10.1002/ijc.33000DOI Listing
October 2020

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition.

Int J Oncol 2020 Jun 30;56(6):1429-1441. Epub 2020 Mar 30.

Cancerology Laboratory, Leloir Institute‑Biochemical Research Institute of Buenos Aires (IIBBA), National Scientific and Technical Research Council (CONICET), Buenos Aires C1405BWE, Argentina.

It is estimated that ~50% of patients with melanoma harbour B‑Raf (BRAF)V600 driver mutations, with the most common of these being BRAFV600E, which leads to the activation of mitogen‑activated protein kinase proliferative and survival pathways. BRAF inhibitors are used extensively to treat BRAF‑mutated metastatic melanoma; however, acquired resistance occurs in the majority of patients. The effects of long‑term treatment with PLX4032 (BRAFV600 inhibitor) were studied in vitro on sensitive V600E BRAF‑mutated melanoma cell lines. After several weeks of treatment with PLX4032, the majority of the melanoma cells died; however, a proportion of cells remained viable and quiescent, presenting senescent cancer stem cell‑like characteristics. This surviving population was termed SUR cells, as discontinuing treatment allowed the population to regrow while retaining equal drug sensitivity to that of parental cells. RNA sequencing analysis revealed that SUR cells exhibit changes in the expression of 1,415 genes (P<0.05) compared with parental cells. Changes in the expression levels of a number of epigenetic regulators were also observed. These changes and the reversible nature of the senescence state were consistent with epigenetic regulation; thus, it was investigated as to whether the senescent state could be reversed by epigenetic inhibitors. It was found that both parental and SUR cells were sensitive to different histone deacetylase (HDAC) inhibitors, such as SAHA and MGCD0103, and to the cyclin‑dependent kinase (CDK)9 inhibitor, CDKI‑73, which induced apoptosis and reduced proliferation both in the parental and SUR populations. The results suggested that the combination of PLX4032 with HDAC and CDK9 inhibitors may achieve complete elimination of SUR cells that persist after BRAF inhibitor treatment, and reduce the development of resistance to BRAF inhibitors.
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http://dx.doi.org/10.3892/ijo.2020.5031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170042PMC
June 2020

Pretreatment Innate Cell Populations and CD4 T Cells in Blood Are Associated With Response to Immune Checkpoint Blockade in Melanoma Patients.

Front Immunol 2020 10;11:372. Epub 2020 Mar 10.

Melanoma Immunology and Oncology, Centenary Institute, Sydney, NSW, Australia.

The development of changes in T cells, referred to as T cell exhaustion, has been suggested as a cause of primary or acquired resistance to immunotherapy by immune checkpoint blockade (ICB). A limited number of studies, largely performed on tumor infiltrating lymphocytes (TILs), has provided evidence in support of this hypothesis, but whether similar changes occur in circulating blood lymphocytes has received little attention. In the present study, a comprehensive analysis of peripheral blood leukocytes from 42 patients taken over the course of treatment with anti-PD-1 was undertaken. The patients included those grouped as responders (who did not progress), primary non-responders (primary resistance) and those with acquired resistance (who initially responded then subsequently progressed). Analysis included surface markers of exhaustion, production of cytokines following stimulation, and assessment of transcription factor levels associated with T cell exhaustion. There were differences in innate cell populations between responders and non-responders at baseline and maintained throughout therapy. Frequencies of total and classical CD14CD16 monocytes were higher and the major subset of NK cells (CD16CD56) was significantly smaller in the primary resistance group compared with responders. However, differences in peripheral blood expression of exhaustion markers were not evident between the treatment groups. T cell exhaustion markers were expressed in practically all patients and the major observation was an increase in CD39 on CD4 T cells during treatment. The results confirm the association of Eomes transcription factor with T cell exhaustion but levels of expression and the ratio with T-bet over Eomes did not differ between the patient groups. Thus, peripheral blood expression of T cell exhaustion markers does not distinguish between responders and non-responders to anti-PD-1 therapy. CD4 T cell expression of IFNγ also differed in pre-treatment samples, indicating that predictors of response unrelated to exhaustion may be present in peripheral blood. The association of response with innate cell populations and CD4 T cell responses requires further study.
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http://dx.doi.org/10.3389/fimmu.2020.00372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076153PMC
March 2021

Do innate killing mechanisms activated by inflammasomes have a role in treating melanoma?

Pigment Cell Melanoma Res 2020 09 20;33(5):660-670. Epub 2020 Feb 20.

Melanoma Immunology and Oncology Group, The Centenary Institute, Royal Prince Alfred Hospital, University of Sydney, Camperdown, New South Wales, Australia.

Melanoma, as for many other cancers, undergoes a selection process during progression that limits many innate and adaptive tumor control mechanisms. Immunotherapy with immune checkpoint blockade overcomes one of the escape mechanisms but if the tumor is not eliminated other escape mechanisms evolve that require new approaches for tumor control. Some of the innate mechanisms that have evolved against infections with microorganisms and viruses are proving to be active against cancer cells but require better understanding of how they are activated and what inhibitory mechanisms may need to be targeted. This is particularly so for inflammasomes which have evolved against many different organisms and which recruit a number of cytotoxic mechanisms that remain poorly understood. Equally important is understanding of where these mechanisms will fit into existing treatment strategies and whether existing strategies already involve the innate killing mechanisms.
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http://dx.doi.org/10.1111/pcmr.12870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497247PMC
September 2020

Shedding light on dabrafenib-induced fevers in patients with melanoma.

Lancet Oncol 2019 12;20(12):1637-1638

Melanoma Oncology Group, Centenary Institute, University of Sydney, Sydney 2050, NSW, Australia.

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http://dx.doi.org/10.1016/S1470-2045(19)30681-3DOI Listing
December 2019

A Th1/IFNγ Gene Signature Is Prognostic in the Adjuvant Setting of Resectable High-Risk Melanoma but Not in Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 04 15;26(7):1725-1735. Epub 2019 Nov 15.

GSK, Rixensart, Belgium.

Purpose: Immune components of the tumor microenvironment (TME) have been associated with disease outcome. We prospectively evaluated the association of an immune-related gene signature (GS) with clinical outcome in melanoma and non-small cell lung cancer (NSCLC) tumor samples from two phase III studies.

Experimental Design: The GS was prospectively validated using an adaptive signature design to optimize it for the sample type and technology used in phase III studies. One-third of the samples were used as "training set"; the remaining two thirds, constituting the "test set," were used for the prospective validation of the GS.

Results: In the melanoma training set, the expression level of eight Th1/IFNγ-related genes in tumor-positive lymph node tissue predicted the duration of disease-free survival (DFS) and overall survival (OS) in the placebo arm. This GS was prospectively and independently validated as prognostic in the test set. Building a multivariate Cox model in the test set placebo patients from clinical covariates and the GS score, an increased number of melanoma-involved lymph nodes and the GS were associated with DFS and OS. This GS was not associated with DFS in NSCLC, although expression of the Th1/IFNγ-related genes was associated with the presence of lymphocytes in tumor samples in both indications.

Conclusions: These findings provide evidence that expression of genes in the TME, as measured by this GS, is associated with clinical outcome in melanoma. This suggests that, using this GS, patients with stage IIIB/C melanoma can be classified into different risk groups.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3717DOI Listing
April 2020

Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy.

Trends Immunol 2019 04 7;40(4):328-344. Epub 2019 Mar 7.

Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Senior author. Electronic address:

Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood. DNA methylation also plays a key role in cytotoxic T cell 'exhaustion' associated with tumor progression. We present an updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes.
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http://dx.doi.org/10.1016/j.it.2019.02.004DOI Listing
April 2019

Five-year outcomes from a phase 3 METRIC study in patients with BRAF V600 E/K-mutant advanced or metastatic melanoma.

Eur J Cancer 2019 03 25;109:61-69. Epub 2019 Jan 25.

University Hospital Essen, Essen, Germany.

Background: Primary findings from the METRIC (TMT212A2301) study demonstrated that trametinib improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in patients with unresectable or metastatic cutaneous melanoma with a BRAF V600 E/K mutation. However, clinical data characterising the long-term use of these therapies in combination with BRAF inhibitors or as monotherapies are limited.

Methods: In this open-label, phase 3 study, 322 patients with BRAF V600 E/K-mutant metastatic melanoma were randomised in a 2:1 ratio to receive trametinib (2 mg orally, once daily; n = 214) or chemotherapy (dacarbazine [1000 mg/m] or paclitaxel [175 mg/m] intravenously, every 3 weeks; n = 108). Patients who progressed on chemotherapy were allowed to cross over and receive trametinib. Five-year results of efficacy and safety analyses are reported.

Results: The median PFS was 4.9 months in the trametinib arm versus 1.5 months in the chemotherapy arm (hazard ratio, 0.54; 95% confidence interval, 0.41-0.73). Landmark OS rates for trametinib versus chemotherapy arms at 1 year, 2 years and 5 years were 60.9% versus 49.6%, 32.0% versus 29.4% and 13.3% versus 17.0%, respectively. Most patients (n = 70 [65%]) from the chemotherapy arm crossed over to the trametinib arm early in their treatment. No unexpected adverse events were reported.

Conclusions: This 5-year follow-up of patients with BRAF V600 E/K-mutant metastatic melanoma on a targeted therapy demonstrates that long-term use of trametinib is possible with no new or unexpected adverse events. Some patients experienced long-term survival benefit with trametinib monotherapy (METRIC ClinicalTrials.gov number, NCT01245062.).
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http://dx.doi.org/10.1016/j.ejca.2018.12.015DOI Listing
March 2019

Marked Global DNA Hypomethylation Is Associated with Constitutive PD-L1 Expression in Melanoma.

iScience 2018 Jun 28;4:312-325. Epub 2018 Jun 28.

Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. Electronic address:

Constitutive expression of the immune checkpoint, PD-L1, inhibits anti-tumor immune responses in cancer, although the factors involved in PD-L1 regulation are poorly understood. Here we show that loss of global DNA methylation, particularly in intergenic regions and repeat elements, is associated with constitutive (PD-L1), versus inducible (PD-L1), PD-L1 expression in melanoma cell lines. We further show this is accompanied by transcriptomic up-regulation. De novo epigenetic regulators (e.g., DNMT3A) are strongly correlated with PD-L1 expression and methylome status. Accordingly, decitabine-mediated inhibition of global methylation in melanoma cells leads to increased PD-L1 expression. Moreover, viral mimicry and immune response genes are highly expressed in lymphocyte-negative plus PD-L1-positive melanomas, versus PD-L1-negative melanomas in The Cancer Genome Atlas (TCGA). In summary, using integrated genomic analysis we identified that global DNA methylation influences PD-L1 expression in melanoma, and hence melanoma's ability to evade anti-tumor immune responses. These results have implications for combining epigenetic therapy with immunotherapy.
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http://dx.doi.org/10.1016/j.isci.2018.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147024PMC
June 2018

SIRT6 haploinsufficiency induces BRAF melanoma cell resistance to MAPK inhibitors via IGF signalling.

Nat Commun 2018 08 24;9(1):3440. Epub 2018 Aug 24.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

While multiple mechanisms of BRAF-mutant melanoma resistance to targeted MAPK signaling inhibitors (MAPKi) have been reported, the epigenetic regulation of this process remains undetermined. Here, using a CRISPR-Cas9 screen targeting chromatin regulators, we discover that haploinsufficiency of the histone deacetylase SIRT6 allows melanoma cell persistence in the presence of MAPKi. Haploinsufficiency, but not complete loss of SIRT6 promotes IGFBP2 expression via increased chromatin accessibility, H3K56 acetylation at the IGFBP2 locus, and consequent activation of the IGF-1 receptor (IGF-1R) and downstream AKT signaling. Combining a clinically applicable IGF-1Ri with BRAFi overcomes resistance of SIRT6 haploinsufficient melanoma cells in vitro and in vivo. Using matched melanoma samples derived from patients receiving dabrafenib + trametinib, we identify IGFBP2 as a potential biomarker for MAPKi resistance. Our study has not only identified an epigenetic mechanism of drug resistance, but also provides insights into a combinatorial therapy that may overcome resistance to standard-of-care therapy for BRAF-mutant melanoma patients.
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http://dx.doi.org/10.1038/s41467-018-05966-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109055PMC
August 2018

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2018 07 13;19(7):916-929. Epub 2018 Jun 13.

UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Background: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting.

Methods: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445.

Findings: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment.

Interpretation: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped.

Funding: GlaxoSmithKline Biologicals SA.
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http://dx.doi.org/10.1016/S1470-2045(18)30254-7DOI Listing
July 2018

Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients with Melanoma Treated with Pembrolizumab.

Clin Cancer Res 2018 10 23;24(20):4960-4967. Epub 2018 Apr 23.

Department of Medicine, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania.

The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal values with no multiplicity adjustment describe the strength of observed associations. Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this analysis. Median BTS was 10.2 cm (range, 1-89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites; all ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs. 23%; < 0.001) and improved OS (HR, 0.38; < 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS ( < 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1-positive tumors were independently associated with higher ORR and longer OS. BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916264PMC
October 2018

CD103 Tumor-Resident CD8 T Cells Are Associated with Improved Survival in Immunotherapy-Naïve Melanoma Patients and Expand Significantly During Anti-PD-1 Treatment.

Clin Cancer Res 2018 07 29;24(13):3036-3045. Epub 2018 Mar 29.

Centenary Institute, the University of Sydney, Sydney, New South Wales, Australia.

Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses, however, occur in less than half of those treated, and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate antitumor immune response. We performed multiparameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy. Increased numbers of CD69CD103 tumor-resident CD8 T cells were associated with improved melanoma-specific survival in immunotherapy-naïve melanoma patients. Local IL15 expression levels strongly correlated with these tumor-resident T-cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset, and these cells significantly expanded early during anti-PD-1 immunotherapy. Tumor-resident CD8 T-cell numbers are more prognostic than total CD8 T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2257DOI Listing
July 2018

Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report.

Cancer Immunol Immunother 2018 Apr 30;67(4):563-573. Epub 2017 Dec 30.

Melanoma Immunology and Oncology Unit, Centenary Institute, University of Sydney, Sydney, Australia.

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4 T cells were profoundly depleted by ATG, while CD8 T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4 T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4CCR6 effector/memory CD4 T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4 rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.
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http://dx.doi.org/10.1007/s00262-017-2107-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860100PMC
April 2018

Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma.

J Clin Oncol 2018 06 28;36(17):1668-1674. Epub 2017 Dec 28.

Caroline Robert, Gustave Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France; Antoni Ribas, University of California, Los Angeles; Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles; Adil Daud, University of California, San Francisco, San Francisco, CA; Jedd D. Wolchok, Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY; Anthony M. Joshua, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston; Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Jeffrey S. Weber, H Lee Moffitt Cancer Center, Tampa; Richard W. Joseph, Mayo Clinic Cancer Center-Florida, Jacksonville, FL; Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia; Hassane Zarour, UPMC Hillman Cancer Center, Pittsburgh, PA; Roxana Dronca, Mayo Clinic, Rochester, MN; Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead; Melanoma Institute Australia, Wollstonecraft; and Macquarie University, MQ Health, Health Sciences Centre; Peter Hersey, University of Sydney, Sydney, New South Wales, Australia; Jin Zhang, James Anderson, Scott J. Diede, and Scot Ebbinghaus, Merck & Co., Inc., Kenilworth, NJ; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA.

Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.
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http://dx.doi.org/10.1200/JCO.2017.75.6270DOI Listing
June 2018

HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma.

Int J Cancer 2018 05 20;142(9):1926-1937. Epub 2017 Dec 20.

The Centenary Institute, University of Sydney, Newtown, NSW, Australia.

Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here, we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient- and in vivo-derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat in 2D and 3D culture systems synergistically induced caspase-dependent apoptotic cell death. Key changes induced by HDAC inhibition included decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases, and cell line dependent upregulation of pro-apoptotic BIM or NOXA together with reduced expression of anti-apoptotic proteins. Independent of these changes, panobinostat reduced c-Myc and pre-treatment of cells with siRNA against c-Myc reduced BRAFi/HDACi drug-induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance mechanisms are due to activation of MAPK-independent pathways.
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http://dx.doi.org/10.1002/ijc.31199DOI Listing
May 2018

Epigenetic modulation in cancer immunotherapy.

Curr Opin Pharmacol 2017 08 10;35:48-56. Epub 2017 Jun 10.

Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, NSW, Australia; Melanoma Institute Australia, Crow's Nest 2065, Sydney, Australia.

The success of immune checkpoint inhibitors in cancer immunotherapy has been widely heralded. However many cancer patients do not respond to immune checkpoint therapy and some relapse due to acquired tumor resistance. Epigenetic targeting may be beneficial in cancer immunotherapy by reversing immune avoidance and escape mechanisms employed by cancer cells, as well as by modulating immune cell differentiation and function. In this manuscript we review recent findings suggesting how epigenetics may be used to improve cancer immunotherapy. We focus on the inhibitors of the CTLA4 and PD1 immune checkpoints and epigenetic modifiers of histone acetylation and methylation and DNA methylation.
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http://dx.doi.org/10.1016/j.coph.2017.05.006DOI Listing
August 2017

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

N Engl J Med 2017 06;376(23):2211-2222

From the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica (M.B.F., D.S.B.H.), and the Departments of Pathology (A.J.C.), Biomathematics (H.-J.W., D.A.E., R.M.E.), and Medicine (D.A.E.), University of California, Los Angeles - both in California; Melanoma Institute Australia and the University of Sydney, Sydney (J.F.T., O.E.N.), Peter MacCallum Cancer Centre, Melbourne, VIC (M.H.), Princess Alexandra Hospital, Brisbane, QLD (B.M.S.), and Newcastle Melanoma Unit, Waratah, NSW (P.H.) - all in Australia; Huntsman Cancer Institute, Salt Lake City (R.H.A., R.D.N.), and Intermountain Healthcare Cancer Services-Intermountain Medical Center, Murray (T.L.B.) - both in Utah; Istituto Nazionale dei Tumori Napoli, Naples (N.M.), Istituto Europeo di Oncologia, Milan (A.T.), and Istituto Oncologico Veneto-University of Padua, Padua (C.R.R.) - all in Italy; H. Lee Moffitt Cancer Center, Tampa, FL (J.S.Z.); Helsinki University Hospital, Helsinki (T.J.); Dallas Surgical Group, Dallas (P.D.B.); Universitair Medisch Centrum Groningen, Groningen (H.J.H.), and Netherlands Cancer Institute, Amsterdam (M.W.J.M.W.) - both in the Netherlands; Norfolk and Norwich University Hospital, Norwich (M. Moncrieff), and Guy's and St. Thomas' NHS Foundation Trust, London (A.M.-R.) - both in the United Kingdom; Swedish Melanoma Study Group-University Hospital Lund, Lund, Sweden (C.I.); University of Michigan, Ann Arbor (M.S.S.); Wake Forest University, Winston-Salem (E.A.L.), and Duke University, Durham (R.S.) - both in North Carolina; Ohio State University, Columbus (D.A.); University of Zurich, Zurich (R.D.), and Centre Hospitalier Universitaire Vaudois, Lausanne (M. Matter) - both in Switzerland; Penn State Hershey Cancer Institute, Hershey (R.I.N.), Thomas Jefferson University (A.C.B.) and Fox Chase Cancer Center (J.M.F.), Philadelphia, and St. Luke's University Health Network, Bethlehem (D.C.D.) - all in Pennsylvania; Greenville Health System Cancer Center, Greenville, SC (S.D.T.); Sunnybrook Research Institute, Toronto (F.W.), and Tom Baker Cancer Centre, Calgary, AB (G.M.) - both in Canada; University of Washington, Seattle (D.R.B.); Saint Louis University, St. Louis (E.H.); Vanderbilt University (D.B.J., M.C.K.), Nashville, and University of Tennessee, Knoxville (J.M.L.) - both in Tennessee; University Hospital Schleswig-Holstein-Campus Lübeck, Lübeck (P.T.), University Hospital of Würzburg, Würzburg (A.G.), and City Hospital of Nürnberg, Nuremberg (E.S.) - all in Germany; SUNY at Stony Brook Hospital Medical Center, Stony Brook (T.L.H.), Memorial Sloan Kettering Cancer Center, New York (C.E.A.), and Roswell Park Cancer Institute, Buffalo (J.M.K.) - all in New York; Northwestern University Feinberg School of Medicine (J.D.W.) and Rush University Medical Center (S.D.B.), Chicago; University of Wisconsin, Madison (H.B.N.); Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (S.S.); M.D. Anderson Medical Center, Houston (J.E.G.); Johns Hopkins University School of Medicine, Baltimore (L.J.); University of Louisville, Louisville, KY (K.M.M.); Dartmouth-Hitchcock Medical Center, Lebanon, NH (R.J.B.); Hospital Clinic Barcelona, Barcelona (S.V.-S.); and Sentara CarePlex Hospital, Hampton, VA (R.A.H.).

Background: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear.

Methods: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis.

Results: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group.

Conclusions: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).
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http://dx.doi.org/10.1056/NEJMoa1613210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548388PMC
June 2017

Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis.

Int J Rheum Dis 2017 Sep 8;20(9):1277-1285. Epub 2017 May 8.

University of Sydney, Sydney, New South Wales, Australia.

Aim: Sarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis.

Methods: Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy.

Results: Immunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1 (CCR6 CCR4 CXCR3 CCR10 ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy.

Conclusion: Our findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.
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http://dx.doi.org/10.1111/1756-185X.13076DOI Listing
September 2017

Whole-genome landscapes of major melanoma subtypes.

Nature 2017 05 3;545(7653):175-180. Epub 2017 May 3.

Melanoma Institute Australia, The University of Sydney, North Sydney, Sydney, New South Wales 2065, Australia.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.
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http://dx.doi.org/10.1038/nature22071DOI Listing
May 2017

Developing an e-learning resource for nurse airway assistants in the emergency department.

Br J Nurs 2017 Feb;26(4):217-221

Senior Lecturer, Centre for Medical Education, University of Dundee.

The aims of this project were to determine the required competencies for a nurse in the emergency department assisting with a rapid sequence induction of anaesthesia (RSI), and to produce a relevant e-learning resource. A three-round multidisciplinary Delphi process produced the following competencies: ability to describe the steps and sequence of events of an RSI, familiarity with the equipment used during an RSI, ability to recognise and help manage problems occurring during an RSI, ability to prepare for an RSI, ability to apply cricoid pressure, and understanding the modification of an RSI in special circumstances. An interactive e-learning package was produced and made available online. Twelve emergency department nurses took part in an evaluation of the e-learning package. All either agreed or strongly agreed that they had increased their knowledge and found the learning useful, and 11 out of 12 nurses reported being somewhat or very confident in the role of airway assistant following completion of the learning.
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http://dx.doi.org/10.12968/bjon.2017.26.4.217DOI Listing
February 2017

Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma.

J Clin Oncol 2016 12 31;34(34):4102-4109. Epub 2016 Oct 31.

Adil I. Daud, University of California, San Francisco, San Francisco; Antoni Ribas, University of California, Los Angeles; Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles; Charlotte Roach and Grant Toland, Dako North America, Carpinteria, CA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston; Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa; Richard Joseph, Mayo Clinic, Jacksonville, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia; Hassane Zarour, University of Pittsburgh, Pittsburgh, PA; Roxana Dronca, Mayo Clinic, Rochester, MN; Jared K. Lunceford, Xiaoyun Nicole Li, Kenneth Emancipator, Marisa Dolled-Filhart, S. Peter Kang, and Scot Ebbinghaus, Merck & Co, Kenilworth, NJ; Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif, France; Anthony M. Joshua, Princess Margaret Cancer Centre, Toronto, ON, Canada; Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia; Richard Kefford, Macquarie University; and Richard Kefford and Peter Hersey, University of Sydney, Sydney, NSW, Australia.

Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.
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http://dx.doi.org/10.1200/JCO.2016.67.2477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562434PMC
December 2016